DESCRIPTION: (Applicant's Abstract) Studies of the living human brain indicate that long-term cocaine abuse alters brain function, and this change may be permanent. Human studies are difficult to interpret, however, because they are often confounded by incomplete and varied drug histories, polydrug abuse, and comorbid psychopathology. Many of these problems can be obviated by the use of animals. Past studies of the functional consequences of cocaine administration in non-human primates have focused on the immediate response to an acute administration of cocaine, whereas long-term changes in functional activity have not been adequately described. Cytochrome oxidase (CO) is an essential enzyme of the mitochondrial electron transport chain that converts fuels into ATP via oxidative phosphorylation. The regional capacity of tissue for oxidative phosphorylation is modified by sustained levels of energy demand that take place over a period of hours, days or weeks and has been repeatedly shown to be linked to persistent changes in neural activity. This activity can be quantitatively visualized in brain tissue sections, and regional values can be determined by quantitative densitometry. Histochemical assessment of cytochrome oxidase activity is an index of long-term cerebral energy metabolism that complements other metabolic mapping techniques such as 2[14C]deoxyglucose that measures short-term, stimulus-evoked changes in metabolic rates. The overall goal of the proposed study is to investigate the long-term effect of cocaine intake on brain function as evaluated in post-mortem tissue from non-human primates that have chronically self-administered cocaine. To that end, the quantitative method of assessing cytochrome oxidase activity that has been developed in the rat will be adapted to non-human primates. Furthermore, the pattern of cerebral energy metabolism resulting from a high and a low dose of self-administered cocaine will be determined in regions of non-human primate brain associated with the effects of cocaine: the striatum and two of its primary limbic inputs, the amygdala and orbitofrontal cortex. The results of the proposed studies will provide a clearer understanding of the comprehensive changes in brain function that result from long-term cocaine abuse.